Parathyroid hormone (PTH) is essential for the maintenance of calcium homeostasis. Low calcium acutely increases PTH release. Chronic hypocalcemia, due to Vitamin D deficiency, or renal failure is thought to stimulate parathyroid cell proliferation with resultant secondary hyperplasia. In primary hyperparathyroidism (adenoma, hyperplasia, or carcinoma) on the other hand, inappropriate hypersecretion of PTH occurs in the presence of an increased serum calcium and parathyroid cell mass. Moreover such pathologic tissue often displays decreased sensitivity to the suppressive effects of calcium on PTH release suggesting an abnormality in both the calcium-regulation of PTH secretion and cellular proliferation. Thus, the total hormonal output from the parathyroid glands is a function of the PTH secretion from individual cells and the total mass of tissue. Despite the clinical and metabolic consequences of hyperparathyroidism, very little is known about what factors regulate parathyroid cell proliferation. Although currently available experimental methods such as dispersed cells, tissue fragments, and organ cultures have greatly enhanced our understanding of PTH biosynthesis and secretion, these techniques are not suitable for studying cellular proliferation. Because cells in culture actively proliferate, cell culture provides a useful approach for quantifying the differential effects of various factors in cellular proliferation. To investigate further the control of hormonal secretion and cellular proliferation, we recently developed a method for establishing cell cultures of bovine and pathologic human parathyroid cells. These cells secrete PTH, proliferate in vivo, and are viable by a number of morphologic and functional criteria. Our specific aims therefore are as follows: 1) To further define the physiologic characteristics of cultured parathyroid cells; 2) To define techniques for modifying the culture environment so as to mudulate the functional characteristics of these cells. 3) To investigate the cellular mechanisms underlying the regulation of PTH release by calcium and finally; 4) To study those factors regulating normal and abnormal parathyroid cell proliferation. These studies may elucidate the mechanisms underlying the alterations in secretion and proliferation in hyperparathyroidism.